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Malaria, Något nytt att berätta?
• Malaria minskar
– men fortfarande 660.000 dödsfall
– Minskning med 25% sedan 2000 (I Afrika 33%)
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Test, Treat and Track !
Diagnos före behandling
Behandling bygger på Artemisininpreparat
Sängnät, Indoor spraying
Läkemedelsprofylax på tapeten igen !
Vaccin inget genombrott
Hot
– Artemisininresistens
– Pyrethrum resistens
Malaria
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Mal Aria – dålig luft
Beskriven 500 BC i Italien
Hippokrates skiljde ut olika febrar: tertiana och quartana
Kinaträdets bark; Mot feber i Peru upptäcktes av spanjorerna på
1600-talet, rek.av Linné mot frossa
• 1880-talet: Myggor för med gift från sumpmarker
• Kring 1900 malariacykeln fastställdes
• Malaraläkemedel krigens läkemedel
– 1930 talet Klorokin anv. av amerikaner 1947
– 1940 talet Proguanil (Paludrin), Pyrimethamin (Daraprim)
Sulphonamide+Pyrimethamine (SP eller Fansidar)
– 1970 talet Meflokvin (Lariam)
• 1990 talet Atovaquone+ Proguanil (Malarone)
• 1970 – 2000 Artemesininpreparat
Malariaprogram
• Malaria eradication - 1955 -1970-tal
• Malaria control - 1980 tal
• Roll Back Malaria – 2001 – ”Halvera morbiditet och mortalitet i malaria
2010 jämfört med år 2000”
– Abudja deklarationen 2000
– Global Fund to Fight AIDS, TBC and
Malaria
– Bill Gates donation
– 2011 nya mål
• Malaria dödlighet i Afrika minskar
Roll Back malaria- Nya mål
2011
• (RBM) targets were updated in June 2011.
– reduce global malaria deaths to near zero by
end 2015;
– reduce global malaria cases by 75% from
2000 levels by end-2015; and
– eliminate malaria by end 2015 in 10 new
countries since 2008,
Malaria 2012
1.8 miljarder US dollar för malaria kontroll 2012
Beräknat behov 5,1 miljarder USD
Malaria 2012
• Antal fall i världen 220 milj
• Döda 650.000
• 56 % av hushåll i Sub Saharan Afrika har
myggnät. De används i 95 % av dessa
• Metoder att minska malariasjuklighet
– Effektiv behandling
– LongLasting Insecticide Nets – Pyrethroids
– Indoor spraying
– IPTp till gravida och små barn IPTi (SP)
Malaria 2013 - Hot
• Minskande eller otillräckliga resurser
• Resistens mot insekticider särskilt
pyrethroids (enda medel i LLIN)
– Har påvisats i 64 länder med malaria
transmission
• Resistens mot Artemisin
– Har påvisats i Thailand, Cambodja, Burma
och Vietnam
Roll Back Malaria
• Test
– Alla fall ska ha en säker diagnos
• Snabbtest eller Microskopi
• Treat
– Behandla med effektiva antimalariamedel i
Afrika; Artemisinin PREPARAT
• Track
– Öka ansträngningar att förhindra nya fall
• Bednets, Indoor spraying, profylax
AKTUELLA DOKUMENT
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The artemisinin story
In the tomb of the Han nobleman, "Marquis of
Dai", living 2200 years ago ….
• Chairman Mao : Find new treatment of malaria !
The chinese army had a problem in the Vietnam war
• 1972; Tu Youyou discovered artemisinin in the
leaves of Artemisia annua (annual wormwood;
kinesisk sommarmalört). The drug is named
Qinghaosu in Chinese.
• It was one of many candidates then tested by
Chinese scientists from a list of nearly 200
traditional Chinese medicines for treating malaria.
It was the only one that was effective, but it was
found that it cleared malaria parasites from their
bodies faster than any other drug in history.
Artemisinin derivat
• Artemether
• Riamet=artemether –lunefantrin ( I Tanzania-ALU)
• Artesunate
• Artemotil
• Dihydroartemisinin
• Kombinationer;
• artesunat+amodiaquine eller mefloquine eller SP
Artemisininderivat vs Kinin
Severe malaria
•Severe malaria is most commonly caused by infection
with Plasmodium falciparum, although P. vivax and
P. knowlesi can also cause severe disease.
–The risk is increased if treatment of an uncomplicated attack
of malaria caused by these parasites is delayed.
–Recognizing and promptly treating uncomplicated malaria is
therefore of vital importance
–Sometimes, however, especially in children,severe P.
falciparum malaria may develop so rapidly that early treatment
of uncomplicated malaria is not feasible.
Severe
Clinical
featuresmalaria
of severe malaria
• impaired consciousness (including unrousable coma);
• prostration, i.e. generalized weakness so that the patient
is unable to sit, stand or walk without assistance;
• multiple convulsions: more than two episodes within 24h;
• deep breathing and respiratory distress (acidotic breathing);
• acute pulmonary oedema and acute respiratory distress
syndrome;
• circulatory collapse or shock, systolic blood pressure
< 80mm Hg in adults and < 50mm Hg in children;
• acute kidney injury;
• clinical jaundice plus evidence of other vital organ
dysfunction; and
• abnormal bleeding.
Severe malaria- lab findings
• hypoglycaemia (< 2.2mmol/l or < 40mg/dl);
• metabolic acidosis (plasma bicarbonate < 15mmol/l);
• severe normocytic anaemia (haemoglobin < 5g/dl, packed
cell volume < 15% in children; <7g/dl, packed cell
volume < 20% in adults);
• haemoglobinuria;
• hyperlactataemia (lactate > 5mmol/l);
• renal impairment (serum creatinine > 265μmol/l); and
• pulmonary oedema (radiological).
Hög andel smittade röda blodkroppar. >2.5% ökar risken
men i högendemiska områden kan man se 20%
Severe malaria
• Pl Falciparum but also Pl Knowlesis
• Microscopy is gold standard
– Few parasites does not rule out severe mal.
– Where microscopy is unavailable or unfeasible, a
rapid diagnostic test (RDT) should be used. RDTs for
detecting HRP2 antigen
• can be useful for diagnosing malaria in patients who have
recently received antimalarial treatment and in whom
bloodfilms are transiently negative for malaria parasites.
– If both the slide and the RDT are negative, the patient
is extremely unlikely to have malaria
Severe Malaria
• Make a rapid clinical assessment, with special
attention to the general condition and level of
consciousness, blood pressure, rate and depth of
respiration and pallor. Assess neck stiffness and
examine for rash to exclude alternative diagnoses.
• Admit the patient to an acute illness ward or room;
or next to the nurses’ station in a general ward for
close monitoring. However if indicated and available,
admit the patient to an intensive care unit.
• Make a rapid initial check of the blood glucose
level, correct hypoglycaemia if present, and
then monitor frequently for hypoglycaemia.
Severe Malaria -Hypoglucaemia
If hypoglycaemia (threshold for intervention, 3mmol/l)
is detected by blood testing or suspected on clinical
grounds, give
Adults:
- 25g of dextrose (preferably as 10% dextrose) over a few
minutes..
• Children
– Immediately give 5ml/kg of 10% dextrose through a peripheral line, and
ensure enteral feeding or if not possible maintain with up to 5ml/kg per
hour of 10% dextrose.
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• Continue to monitor blood glucose levels (with a
rapid ‘stix’ method if available) in order to regulate the
dextrose infusion. Remember that hypoglycaemia may
recur even after treatment with intravenous dextrose.
Artesunate – new recommendation
april 2011
• The AQUAMAT trial, Lancet 2010; 376: 1647–57
• a multi-centre study conducted in African children
hospitalized with severe malaria. This very large
randomized controlled trial, which enrolled 5425 children
< 15 years of age across Africa,
• a significant mortality reduction by 22.5% in the
artesunate group when compared to the quinine group.
• The incidence of convulsions, coma, and hypoglycaemia
developing after hospital was also significantly reduced.
• Importantly there was no significant difference in the
incidence of severe neurological sequelae
Severe malaria
anti – malaria treatment
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For adults and children, artesunate 2.4 mg/kg body weight IV or IM
given on admission (time = 0), then at 12 h and 24 h, then once a day is
the recommended treatment.
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Artemether, or quinine, is an alternative if parenteral artesunate is not
available:
– artemether 3.2 mg/kg BW IM given on admission then 1.6 mg/kg BW per
day ; or
– quinine 20 mg salt/kg BW on admission (IV infusion or divided IM
injection), then 10 mg/kg BW every 8 h; infusion rate should not exceed 5
mg salt/kg BW per hour.
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Give parenteral treatment for 24 h.
– complete treatment by giving a full course of oral artemether plus
lumefantrine or other available combination
– Broad spectrum Antibiotics also indicated to all cases of
severe malaria
Pre referral treatment of severe
malaria
• If complete treatment for severe malaria is not
possible patients with severe malaria should be
given pre-referral treatment and referred immediately
to an appropriate facility for further treatment.
• – The following are options for pre-referral treatment:
rectal artesunate • quinine IM • artesunate IM
artemether IM.
• – In young children of less than 5 years of age, the use
of the use of rectal artesunate (10 mg/kg) has been
shown to reduce the risk of death and permanent
disability.
Severe malaria – pregnant women
• Increased risk
– Hypogkucemia and pulmonary oedema
– Mortality rate 50%
– Artesunate is the drug of choice.
– If this is not available, artemether is referable
to quinine in later pregnancy because
– quinine is associated with a 50% risk for
hypoglycaemia
Severe malaria-seizures
• Treat seizures with a benzodiazepine (intravenous
diazepam,). If a seizure episode persists longer than
10min after the first dose, give a second dose of a
benzodiazepine
– Total dose benzodazepim 1 mg/kg per 24 h
• Seizures that persist (status epilepticus) despite the use
of two doses of benzodiazepam, give phenytoin
– Phenytoin (Epanutin) 18mg/kg body weight intravenously, or
– Phenobarbitone (Fenemal)15mg/kg body weight intramuscularly
or intravenously if it is the only available option.
• Monitor breathing repeatedly. High dose of phenobarbitone
(20mg/kg body weight) has been linked to an increased risk for
death and the patient may need assisted ventilation.
Treatment of uncomplicated
malaria
Artemisinin-based combination therapies (ACTs) are the recommended
treatments for uncomplicated P. falciparum malaria. Fixed
combinations för three days
■ artemether plus lumefantrin ALU (Riamet) Adults 4 tabl 6 trimes
0,8,24,36,48 and 60 h
• The recommended treatment is a 6-dose regimen over a 3-day period.
• (5–14 kg: 1 tablet; 15–24 kg: 2 tablets; 25–34 kg: 3 tablets; and > 34 kg: 4
tablets),
• given twice a day for 3 days.
• Other ACT
■ artesunate plus amodiaquine,
■ artesunate plus mefloquine,
■ artesunate plus sulfadoxine-pyrimethamine,
■ dihydroartemisinin plus piperaquine.
Malaria - behandling
• Nytt hopp för Klorokin ??
– Malawi var 50% av allla Pl falc. Resistenta
1993 mot klorokin
– Helt stopp i användningen av klorokin
– Molekylär markör för klorokinres borta 2001
– 2006 jmf studie 210 barn medd okomplicerad
malaria.
• Klorokin failure 1 /80.
• Fansidar failure 71/87
• Malariavaccin
RTS S vaccin
Sporocoitantigen kopplat till
HBsAg och adjuvans AS01
Utvecklat av GSK
Melinda o Bill Gates har satsat
miljarder
Malariavaccin projekt
Malaria vaccin
Strategic goal
• By 2025, develop and license
a malaria vaccine that has a
protective efficacy of more than
80% against clinical disease and
lasts longer than four years.
Landmark
• By 2015, develop and license a
first-generation malaria vaccine that
has a protective efficacy of more
than 50% against severe disease
and death and lasts longer than
one year.
The current status of malaria vaccine research
WHO Nov 2012
• No licensed malaria vaccines.
• Over 20 vaccine in clinical trials.
• The vaccine RTS,S/AS01
•against Plasmodium falciparum, with no
protection expected against P. vivax malaria.
•a partnership between GlaxoSmithKline
Biologicals and
•Malaria Vaccine Initiative (MVI), with funds
from the Bill & Melinda Gates Foundation.
•The clinical testing of RTS,S is at least 5-10
years ahead of other candidate malaria
vaccines.
Malariavaccin RTS,S/AS01
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Sporocoitantigen
Hepatit B s antigen (HBsAg)
Ny och potent adjuvans
Fas 3 studie startade 2009
– 15460 barn inkluderade’
– Sju länder i Sub-Saharan Africa
– Kontrollgruppen fick Meningokock eller
Rabies vaccin
RTS,S/AS01 delstudie 5-17 mån vid dos 1
3 doser 1 mån intervall
Follow-up 12 mån efter sista dos
N Engl J Med 2011; 365:1863-1875 Nov 17 2011
• Incidence of the first or only episode of clinical
malaria was 0.44 per person-year in the
RTS,S/AS01 group and 0.83 per person-year in the
control group (Rabies vaccin, per protocol analysis)
• efficacy against clinical malaria 55.8%
• severe malaria 47.3%
– The efficacy over a 4-year period was 16.8%. Efficacy
declined over time and with increasing malaria exposure.
(Tidig studie i Kenya)
• Ingen skillnad i dödlighet mellan grupperna
• Samma frekvens biverkningar men fler krampanfall i RTS,S gruppen
RTS,S/AS01, delstudie 6-12 veckor vid dos 1
3 doser, 1mån intervall
Follow up 12 mån efter första dos
N Engl J Med 2012; 367:2284-2295 December 13, 2012
• The incidence of the first or only episode
of clinical malaria was 0.37 per personyear in the RTS,S/AS01 group and 0.48
per person-year in the control group,
(Meningokockvaccine, per protocol analysis)
• efficacy against clinical malaria 31.3%
• against severe malaria 36.6%
– Adverse events similar frequency
– Meningitis 9/4358 vs 2/2179